Advanced Glycation End-products (AGEs) are a heterogeneous group of compounds formed via the nonenzymatic glycation of lipids, proteins and nucleic acids. AGEs form endogenously during normal metabolism, and exogenously from foods processed at a high temperatures and tobacco smoking. N5- (carboxymethyl)-lysine (CML)-AGE is one of the best characterized AGEs. The accumulation of AGEs in the human tissues accelerates under hyperglycemia. AGEs trigger oxidative stress and inflammation by interacting with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) neutralizes the reactions mediated by the RAGE and therefore, acts as an anti-inflammatory factor. We recently reported that levels of sRAGE significantly predicted a lower risk of colorectal cancer (CRC) in Finnish male smokers. The role of AGEs and sRAGE in CRC development has not been investigated in women. We hypothesize that AGEs contributes to CRC development while sRAGE exerts a protective effect. We propose a case-cohort study that builds upon three NIH-funded studies conducted within the Women's Health Initiative (WHI) Observational Study of a cohort 93,676 postmenopausal women. The proposed study includes 425 incident CRC cases and 791 randomly selected subcohort participants. The study has three specific aims: 1) To examine the association between baseline fasting circulating levels of CML-AGE, sRAGE, and the sRAGE/CML ratio and risk of subsequent development of CRC;2) to examine the independent predictors of circulating levels of CML-AGE and sRAGE among the subcohort participants, including age, body mass index, alcohol use, daily average intake of nutrients (e.g., carbohydrate nutrients and fatty acids), and tobacco smoking;and 3) to explore the inter-relationships among circulating levels of CML-AGE, sRAGE and serological markers of insulin resistance, inflammation and estradiol on the risk of CRC. The availability of pre-diagnostic bio-specimens and exposure information, as well as previously measured analytes, makes this study highly feasible and efficient. The long- term goal of this research is to elucidate a modifiable pathway, AGEs/RAGE, that may connect environmental exposure (e.g., dietary intake), inflammation, and insulin resistance with CRC etiology and prognosis. PUBLIC HEALTH RELEVANCE: The importance of the AGEs/RAGE axis in CRC development has not been investigated in women. The findings from this study may lead to identification of potentially modifiable risk factors for CRC and biomarkers for monitoring disease progression. PUBLIC HEALTH RELEVANCE: Advanced glycation end-products (AGEs) are sugar adducts to proteins that form and accumulate under conditions of hyperglycemia. Binding of AGEs with the receptor for AGEs (RAGE) promotes oxidative stress and inflammation and soluble RAGE can block such effects. This application sets out to examine whether AGEs increase colorectal cancer risk and soluble RAGE play a protective role in colorectal cancer development among postmenopausal women in the Women's Health Initiative Observational Study.